Animal Models in Syndromes of Accelerated Arteriosclerosis

Basic Science SECTION EDITOR. Bruce L. Gewertz, M D

Animal Models in Syndromes of Accelerated Arteriosclerosis Yehuda G. Wolf;MD, S. David Gertz, MD, PhD, and Shmuel Banai, MD, Jerusalem, Israel, and Stanford, Califarnia

INTRODUCTION Accelerated arteriosclerosis constitutes the most important limitation to prolonged patency after mechanical revascularization of vascular occlusive disease. In recent years, percutaneous revascularization procedures have become the most popular approach for treatment of coronary atherosclerotic occlusive disease. Although the initial success rate is high (>95%),a significant proportion (20-50%) develops restenosis within 6 months. 1-4 Accelerated arteriosclerosis and intimal hyperplasia are also the major threat to long-term patency of coronary and peripheral surgical arterial reconstructions and bypass graftsq5Despite the high prevalence of restenosis and intimal hyperplasia, there is no clinically effective treatment. Furthermore, considerable controversy persists regarding its pathogenesis in humans6 with the vast majority of data having been derived from animal studies. Between 1980 and 1994 over 50 clinical trials were unsuccessful in limiting restenosis7 despite the fact that many of the agents investigated were reported to be effective in animal models. One striking example is the angiotensin-converting enzyme inhibitor cilazapril. The drug was effective in rats,' rabbits, and guinea pigs' but was ineffective in pigs" and baboons" and did not reduce the inciFrom the Department of Vascular Surgery, Hadassah University Hospital, Israel, and the Division of Vascular Surgery, Stanford University Medicdl Center, Stanford, CA, (Y.G.W.), Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel, (S.D.G.), and Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel. Correspondence to: Y.G. Wag MD, Division of Vascular Surgery, Stanford University Medical Center, 300 Pasteur Drive, #3642, Stanford, CA 94305-5642, USA. 328

dence of restenosis in two large clinical randomized studies in Europe and the United States.'2r13Such discrepancies have focused attention on the validity and relevance of various animal models to syndromes of accelerated arteriosclerosis in humans. Our objective here is to review the merits and shortcomings of animal models designed to investigate syndromes of accelerated arteriosclerosis, while focusing on the obstacles to successful modeling of the human disease.

PATHOGENESIS Syndromes of accelerated arteriosclerosis are triggered by injury to the vessel wall. The stereotypic response of the vascular wall to injury is intimal hyperplasia which occurs in varying degrees in all of these syndromes. This process is characterized by migration and proliferation of activated smooth muscle cells from the media to the intima and production of abundant extracellular matrix that result in intimal thickening and luminal compromise. 1411 Intermediate-term and late failure of surgical reconstructions including arterial anastomoses, l 6 vein grafts, 17T18 arteriovenous dialysis grafts, l 9 and arteries subjected to endarterectomy2' or to Fogarty balloon thrombectomyZ1 are due primarily to intimal hyperplasia. Balloon angioplasty in clinical practice is applied to arteries with advanced atherosclerosis and usually results in more severe arterial injury than routine surgical handling. It includes stretching of the tissues of the arterial wall, disruption of the endothelium, and plaque rupture with tears through the intima, internal elastic membrane, and media.22f23 Mechanisms of restenosis after such intervention include elastic formation, and organization of mural t h r o m b ~ s , intimal ~' hyperplasia, and constrictive arterial remodeling.26 The relative impor-

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Animal models for accelerated arteriosclerosis 329

Fig. 2. An atherosclerotic rabbit iliac artery, 4 weeks after balloon injury (Movat stain). Notice the massive circumferential infiltration of foam cells in the outer media and in the thick intimal lesion. An area of injury to the intestinal elastic lamina and irregularity of the neointimal medial boundary is seen in the upper portion of the vessel.

DIFFICULTIES I N MODELING INTIMAL HYPERPLASIA AND RESTENOSIS Fig. 1. A A normal rat carotid artery (H6E). Notice four

Ideally, restenosis research should be performed on arteries with advanced atherosclerotic disease. Such animal models are very difficult to produce. They require a prolonged period of maintenance on atherogenic diet in species that are susceptible to atherosclerosis, and, possibly, the use of specific genetic strains. Even then, the characteristics of the atheroma may be quite different from that of humans. After the injury, evaluation of the response of the vessel wall should be carried out at several time points over a period of several months. It is clear, tance of arterial remodeling is unresolved. Recent therefore, that reliable simulation of human restedata from and intravascular ultrasound nosis requires lengthy and very expensive experi(IVUS) data from humans26 have suggested that ments. late lumen loss after balloon angioplasty is related In practice, restenosis research has been domito changes in vessel wall circumference. However, nated by logistic considerations. Most importantly, other studies in atherosclerotic rabbits have sugthe time periods studied have been much shorter gested that despite the presence of constrictive and than those observed in the clinical setting. Atheroexpansive remodeling, neointimal formation is still sclerosis, which progresses in humans over a lifethe principal determinant of luminal narrowing.29 time, is induced in rabbits by feeding 2% cholesThe use of stents has increased dramatically in reterol, 6% peanut oil, which increases cholesterol cent years, and their application has virtually eliminated elastic recoil and late remodeling.3t4Howlevels 20- to 25-fold for 1 month.33It may therefore ever, it has not prevented restenosis, and intimal be inappropriate to attribute morphological differhyperplasia continues to narrow the lumen by ences between human and rabbit atheromatous legrowth of tissue between the stent s t r ~ t s . ~ O - ~ ~ sions solely to species difference. The duration of Allograft arteriosclerosis has many features in follow-up after the injury in most studies has been common with the above diseases but is further 2-4 weeks while restenosis and intimal hyperplasia complicated by host-graft immunological interacin clinical practice occur over a period of 3-6 months. Some of the observed differences between tions, which will not be discussed here. elastic laminae and a flat layer of endothelial cells lining the luminal aspect of the internal elastic lamina (which defines the boundary between the media and the intima). B A rat carotid artery, 4 weeks after balloon injury (horseradish peroxidase complex and hematoxylin) . Note the thick neointimal lesion overlying the internal elastic lamina.

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Table I. Animal models in syndromes of accelerated atherosclerosis ~

~~

~

~~

~~

Animal

Advantages

Disadvantages

Representative models

Mouse

Inexpensive, many genetic sequences described, many specific strains available, most suitable for transgenic models and gene kno~k-out,~' very small amounts of reagents required

Minute arteries require modification of injury, less well characterized, requires microsurgery, dissimilarity with human arteries

Carotid, guidewire injury5' Carotid closed compression and rolling5' Carotid, perivascular electric injury5' Carotid, perivascular cuff53

Rat

Most commonly used, best characterized,14,15 low cost, easy handling and robust, many known nucleotide sequences, availability of syngeneic immune-deficient strains,54and transgenic ratss5

Absence of developed intima Carotid balloon injury, Fogarty 2Fi4,15 and anatomic dissimilarity with human arteries, Carotid air d e s i c ~ a t i o n ~ ~ Femoral, transluminal light surgical models require activation of microsurgery, photochemical dyes5' hypercholesterolemia Aortic balloon injury, difficult to induce and resistant to atheroscler~sis,~~ Fogarty 3F or 2F39r60 Epigastric vein-femoral the role of thrombus is very artery interposition61 limited and a single layer of Carotid jugular platelets forms57 interposition"'

Rabbit

Well susceptible to hyperlipidemia-induced atherosclerotic lesion^,^^,^^ heritable hyperlipidemic (Watanabe) strain available,64 organized thrombus present after balloon injury,65 size of iliac arteries similar to human coronary arteries, and evaluation of human coronary and peripheral devices possible.66

Anatomic dissimilarity with human arteries, atherosclerotic lesions different from human lesions with concentric foam cell infiltration of media and intima and prominence of lipid-laden macro phage^,^^,^^ very vasoreactive with occasional abrupt closure6'

Dog

Readily available, coronary anatomy similar to that of humans, and coronary procedures possible;79 much cardiovascular work done, evaluation of devices for human use.80*81

Difficult to induce hypercholesterolemia and resistant to atherosclerosis,56~82 increase fibrinolysis compared to humans,49significantly less coronary neointimal thickening than in pigs.80*83

Aortoiliac balloon injury, Fogarty 3F68 Femoral balloon injury, 3 mm69 Thoracic aorta balloon injury, Fogarty 4F7' Carotid balloon injury, Fogarty 2F or 3 mm71,72 Ear artery Aortoiliac chronic indwelling catheter74 Carotid-jugular vein interp~sition~~ Chronic electric stimulation of Air dessication of femoral Carotid, perivascular cuff78

the animal models and human disease may be attributable to the type of injury, the artery selected for experimentation, and the duration of follow-up. Most short-term studies have focused on one aspect of intimal hyperplasia-most commonly,

Coronary balloon injury and stent 3.0-3.5 mm80.81

Carotid balloon injury, Fogarty 4Fs4 Aortic balloon injury, 10-18 mms5 Carotid endarterectomys6 Femoral arteriovenous graftss7

smooth muscle cell proliferation-and these studies were often performed in previously normal arteries. The typical rate of smooth muscle cell proliferation that has been observed in such experiments has been considered by some to be much higher than

A n i m a l models for accelerated arteriosclerosis 33 1

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Table I. Continued Animal

Advantages

Disadvantages

Representative models

Pig

Easy handling, lipid metabolism and lipoprotein profile well investigated and similar to that of humans,” development of spontaneous atherosclerosis without cholesterol feedings9 and of complex lesions in a strain with inherited hyper-LDL ch~lesterolemia,~~ platelet aggregation similar to that of humans,” availability of von Willebrand factor-deficient pigs,” after arterial injury platelet thrombus and fibrin deposition occur,92 histological similarity of neointima to human lesions,93 useful for investigation of human coronary devices

Rapid weight gain, expensive maintenance, susceptible to ventricular fibrillation during coronary occlusion94

Carotid balloon injury, Fogarty 4 F or 8 mm92,95 Femoral balloon injury, 3-4 mm96 Coronary balloon injury, 3 mm93 Coronary oversized stem9’

Nonhuman primates (apes, baboons, and monkeys)

Lipid metabolism and lipoprotein profile similar to that of humans98 but response to atherogenic diet varies in different species99may develop obstructive, complex atheromatous plaques similar to those of humansloo as well as remodeling”’

Very sensitive, care requires wide knowledge base, difficult to handle, very expensive,lo2 limited use due to logistic difficulty and NIH restriction^,^^ no studies on coronary artery injury

Lower-extremity artery angioplasty I I, ’O Carotid e n d a r t e r e ~ t o m y ’ ~ ~

that observed in humans.34r35While such experiments provide much information about the arterial response to injury, they do not include the morphologic and pathogenetic complexities of the human condition. Extracellular matrix forms the bulk of the late (beyond 4 weeks) intimal lesion in various species and in human restenotic lesion^.^^.^' The late dissociation between the decreasing rate of smooth muscle cell proliferation and the continued increase in the size of the intimal lesion has been well described.l 5 However, research related to extracellular matrix biosynthesis and its control has lagged considerably, in part because of technical difficulties in measuring its rate of production and identifying its constituents, 3 9 and partly because accumulation is much more prominent later in the process beyond the usual duration of animal experiments. In addition, although syndromes of accelerated arteriosclerosis are often grouped together, their pathological features are not identical, which further emphasizes the need for critical evaluation of the applicability of specific experimental model sys-

tems and the necessity to define precisely what aspect of the disease process is being studied.

INTERSPECIES DIFFERENCES RELEVANT TO VASCULAR DISEASE Elastic arteries from various species have been reported to demonstrate remarkable structural similarity in the number of lamellar units per arterial radius and the average tension per lamellar unit.40 Muscular arteries, particularly the coronary arteries, exhibit major differences between species. Medial elastin content is low in small animals but higher and close to human level in larger animals such as baboons, dogs, and pigs.*l In smaller animals, such as rats and rabbits, the intima consists of the endothelium and the narrow acellular space underlying it (Fig. 1).In larger animals the intima is thicker and more cellular, but only in human coronary arteries is spontaneous thickening of the intima at an early age reported to occur with discontinuity of the internal elastic lamina and patches of endothelial d e n ~ d a t i o n These . ~ ~ differences have

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direct relevance to intimal hyperplasia. Smooth muscle cell migration from the media to the intima is a pivotal event in rodent intimal h y p e r p l a ~ i aIt. ~ ~ has been suggested that in arteries with intimal smooth muscle cells (most large and medium-sized arteries in humans), such migration may not be as crucial to intimal hyperplasia and that part of the smooth muscle cell population within the lesion may stem from intimal cells.34 Atherosclerotic lesions in experimental animals may differ substantially from the clinically significant lesions observed in humans. It is customary to point out that in rabbits, stenotic intimal lesions, which result after balloon injury and highcholesterol diet, are concentric with abundant foam cells and quite distinct from the common human lesion (Fig. 2). Nonetheless, foam cell infiltration is often focal with adjacent areas consisting primarily of fibrous tissue, which bears striking similarity to advanced human lesions.44 The method of induction of these atherosclerotic lesions is harsh and brief and the characteristics of the lesion may be primarily related to the method of induction rather than to the species difference. For similar reasons, experimental atherosclerotic lesions in many species do not reach the stage of actual s t e n ~ s i s . ~ ' Complex atherosclerotic obstructive plaques, similar to clinically significant lesions in humans, have been produced experimentally only in hyperlipemic pigs46 and in subhuman primates.47

EXPERIMENTAL INJURY Choice of Species Early experimental work on intimal hyperplasia was most commonly performed on rats and rabbits, which are inexpensive and sturdy. Anatomic differences between these small animals and human arteries, and repeated clinical failures of agents that were effective in small animals have led to recommendations to examine agents in large animals and in more than one specie^.^' Nonhuman primates are phylogenetically closest to humans but are extremely expensive and sensitive. Dogs have been used extensively, especially for investigation of interventional and implantable devices intended for human use, but dissimilarities between the canine and human coagulation systems must be considered.49Recently, the pig has been perceived as an appropriate and relatively practical model, particularly for studies on the coronary circulation, and has been used in numerous studies. Interest in murine vascular injury has increased recently because of the availability of transgenic models and gene knock-out experiment^.^'

The principal advantages and disadvantages of the various species and frequently used model systems are listed in Table I.5'-'04

Choice of Artery Elastic arteries (the aorta and its main branches) and muscular arteries (e.g., femoral and coronary arteries) have been reported to differ in medial elastin content, in proteoglycan composition, l o 5 in smooth muscle cell subpopulations, and in intravascular ultrasound appearance'" (Figs. 3 and 4). Nonetheless, very little information exists concerning the specific differences between these two types of arteries in the response to injury. The site and size of the studied artery dictate to some extent its preferred use. Superficially placed arteries, such as the carotid and femoral arteries, afford relatively easy surgical exposure, while deeper arteries, including the coronary arteries, are best approached with a fluoroscopically guided, percutaneous catheter. Devices intended for human use are usually applied to larger arteries such as the iliac arteries in the rabbit'" and the coronary or peripheral arteries the dog and the pig. Introduction of such devices may require large, straight arteries such as the carotid arteries which are used to access the coronary circulation in minipigs'" and the iliac arteries in rabbits."' Although considered the most relevant model of clinical angioplasty, balloon injury of atherosclerotic arteries is expensive and cumbersome and, consequently, most information concerning the arterial response to injury has been derived from previously healthy arteries.' l 1 An important theoretical disadvantage of this approach is that it does not simulate the early cellular responses to vascular intervention in humans. Angioplasty or surgical manipulation are applied as a rule to severely diseased arteries where large populations of cellular elements in the diseased wall, particularly smooth muscle cells, may be already in the activated state and may react differently to injury than normal, quiescent cells in the healthy artery. An attempt at getting closer to the clinical state without inducing atherosclerotic lesions is the double or repeat injury. Here, the first injury serves to activate the cells and create a "diseased" l2

'"

Method of Arterial Injury The most commonly employed method for arterial injury in small animals is balloon-withdrawal injury. An inflated Fogarty balloon catheter is commonly withdrawn several times to cause endothelial denudation and medial injury.15 Alternatively, an oversized angioplasty balloon may be inflated to

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Animal models for accelerated arteriosclerosis 333

comparable acute gain in luminal diameter.72 The degree of intimal hyperplasia as measured by intima-to-media area ratio or luminal cross-sectional area narrowing by neointima is usually proportional to the injury as assessed histologically, 113r114 to the shear force and number of successive injuries applied,84 and to the inflation pressure and degree of oversizing of angioplasty balloon.' l 5 These relationships have been reported to vary among species, thus the injury-neointimal thickness regression slope is steep in pigs, intermediate in baboons and rabbits, and almost flat in Other forms of arterial injury include overdistention with coils or stents, which induce intimal hyperpla~ia,"~ while distension with fluid alone has not been shown to result in significant neointima l 6 The nylon loop technique has been f~rmation.~'" reported to cause injury limited to the endothelium with only mild or no injury to the media and a limited neointimal r e ~ p o n s e . " ~ Air dessication has also been used to injure the endothelium in rabb i t ~ 'and ~ in rats5' and induces significant intimal hyperplasia. Less commonly employed techniques include a chronic indwelling aortic catheter in rabb i t and ~ ~electrical ~ stimulation of the arterial wall in rabbits, rats, and Surgical removal of the intima in dogs"' and removal of the adventitia of the abdominal aorta i n rats12' have also been employed to induce intimal hyperplasia. Perivascular cuffing has been shown to induce a neointimal proliferation in and rabbit^,^' and photochemical injury has been shown to result in endothelial denudation and intimal hyperplasia in rats.59 External crushing of the ear artery in the rabbit results in a marked predictable neointimal proliferation but with more intense adventitial inflammatory response than after intraluminal injury.73 Fig. 3. Porcine carotid arteries (Movat stain). A A normal artery. Notice the numerous elastic laminae and compare to the carotid artery of the rat in Figure 1. B An artery with a neonatal lesion, 4 weeks after balloon injury. Fig. 4. A porcine femoral artery 4 weeks after balloon injury (Movat stain). Note the paucity of elastic tissue and elastic laminae compared to the porcine carotid artery in Figure 3. The neointima overlies a prominent tear in the internal elastic lamina.

6-1 2 atm pressure for 30-120 ~ e cThe . ~latter ~ technique is usually employed in larger animals, often in association with fluoroscopic guidance. The Fogarty embolectomy catheter has been shown to induce more intimal hyperplasia and proliferation than a dedicated balloon angioplasty catheter at

DRUG DELIVERY Systemic delivery of drugs has been the most common method to evaluate agents designed to attenuate experimental restenosis or intimal hyperplasia. However, local delivery of agents has recently attracted considerable attention. Important advantages of the latter include increased concentration of the drug at the site of injury, prolonged local activity, decreased systemic effects, and conservation of expensive medication.12' A variety of possibilities for local delivery have been evaluated in animal models. Perivascular delivery results in diffusion of the drug primarily through extravascular and adventitial capillaries and has been shown to produce a high concentration of the applied agent in the arterial wall in rats.'22 Differences in arterial

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wall thickness and quantity of vasa vasorum make extrapolation of such findings to humans problematic. Medication may be administered continuously by means of a pump into the perivascular space'23 or released by degradable 124 or nondegradable 12' polymeric matrices that may be wrapped around the vessel. Perivascular delivery requires surgical exposure of the blood vessels and is therefore of lesser clinical potential than intraluminal delivery, which is applicable to catheter-based procedures. Intraluminal delivery may be achieved through specially designed porous balloon catheters or released from polymer-coated intravascular stents.'26 Penetration of the agent into the arterial wall depends in part on the type of artery and species as well as on the severity of atherosclerosis, and the injury induced prior to delivery. In general, thinner arteries require lower infusion pressures for histologically similar depth of penetration. 126 Local delivery devices have been evaluated in rabbit iliac arteries,'27 dog iliac and coronary arteries,I2' and in pig femoral and coronary arteries.96p129 Other therapeutic modalities against restenosis include radiotherapy, which has enjoyed a recent surge of i n t e r e ~ t , ' ~ O -and ' ~ ~gene transfer, which is continuing to be developed in animals toward the goal of clinical a p p ~ i c a t i o n . ' ~ ~

CONCLUSION Clinical failures of antirestenosis agents that have been effective in experimental animals have underscored the limitations of commonly used animal models for simulating the human disease. Animal models have been used successfully for studying specific aspects of the early phase of the restenotic process (e.g., smooth muscle cell proliferation). However, little has been accomplished in understanding the biology of vascular wall remodeling, its relationship to intimal hyperplasia, and its role in long-term models of restenosis and accelerated arteriosclerosis in experimental animals and in humans. In general, rodent models have been used for screening studies and molecular work while large animals have been employed for preclinical studies of drugs and devices. As long as restenosis research is dominated by logistic considerations employing short-term experiments to evaluate early postinjury changes, extrapolation to human disease will remain probIematic. Consequently, short-term animal models should be perceived as simulating only specific facets of the process, and the model used should be tailored to the specific aspect investigated. More long-term studies are necessary to resolve the still inadequately deciphered relation be-

Annals of Vascular Surgery

tween intimal hyperplasia, vascular wall remodeling, and restenosis; clarification of this relation appears to be essential to further our understanding of the pathogenesis of this entity in humans. REFERENCES 1. Topol EJ, Leya F, Pinkerton CA, et al. A comparison of

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